Abstract 82TiP
Background
Addressing resistance to 1st generation (gen) selective RET inhibitors (SRIs) is an area of high unmet need, with a number of RET dependent and independent pathways identified1,2. The ideal profile of a next gen SRI has been proposed: broad activity against RET fusions/mutations, inhibition of both V804M/L gatekeeper and G810C/S/R solvent front mutations and penetration of the CNS to address brain metastases1,2. This trial is evaluating whether EP0031, an orally available next gen SRI, can address resistance to 1st gen SRIs and improve on their clinical profile.
Trial design
This phase I/II study is recruiting up to 265 patients with NSCLC, thyroid cancer or other solid tumours with RET aberrations. The 1st part of the study is a dose escalation to investigate safety, tolerability, PK and PD and to define the maximum tolerated dose (MTD) and/or Recommended Phase II Dose (RP2D). Dose escalation is based on a rolling 6 design and is expected to recruit up to 40 patients. Once an RP2D is established, expansion cohorts of approximately 25 evaluable patients each will further explore the safety and tolerability of EP0031, and provide preliminary efficacy data in selected patient populations with RET-altered tumours with/without prior 1st gen SRI therapy: Four cohorts of patients with NSCLC and medullary thyroid cancer Two cohorts of patients with other solid tumours, including differentiated thyroid cancer. Key inclusion criteria are as follows: Male or female ≥ 18 years of age, with a diagnosis of an advanced solid tumour with documented RET altered malignancy ECOG Performance Status of 0 or 1 at screening with no deterioration over the previous 2 weeks. For expansion cohorts patients must have a solid tumour measurable by RECIST v1.1, with/without asymptomatic, stable brain metastases Recruitment was initiated in the US in November 2022 and is expanding to centres across Europe. A parallel phase I/II trial is ongoing in China (A400, NCT05265091, Kelun Biotech).
1Annals of Oncology 32(2) 261 (2021).
2Journal Thoracic Oncol 15(4) 542 (2020).
Clinical trial identification
NCT05443126.
Legal entity responsible for the study
Ellipses Pharma.
Funding
Ellipses Pharma.
Disclosure
A.G. Gianoukakis: Non-Financial Interests, Institutional, Writing Engagements: ATA Medullary thyroid cancer guidelines writing group; Non-Financial Interests, Institutional, Principal Investigator: Ellipses Pharma. S.M. Arnold: Non-Financial Interests, Institutional, Principal Investigator: Ellipses Pharma. S.A. Kahn: Non-Financial Interests, Institutional, Principal Investigator: Ellipses Pharma; Financial Interests, Personal and Institutional, Advisory Board, Also receives speaker fees: Eisai, Foundation Medicine. M. Taylor: Financial Interests, Personal and Institutional, Advisory Board, Also a speaker's role and receives research funding: Bristol Myers Squibb, Eisai Inc, Merck; Financial Interests, Personal and Institutional, Advisory Board: Novartis, Pfizer, Bayer, Sanofi/Genzyme, Regeneron, LOXO oncology, Exelixis, Cascade Prodrug; Financial Interests, Personal and Institutional, Advisory Board, Also a speaker's role: Blueprint Medicines; Financial Interests, Personal and Institutional, Advisory Board, Also receives research funding: Immune-Onc Therapeutics; Non-Financial Interests, Institutional, Principal Investigator: ISA Therapeutics, Simcha; Non-Financial Interests, Personal and Institutional, Principal Investigator: Ellipses Pharma. E. Garralda: Financial Interests, Personal, Advisory Board: Genentech, F.Hoffmann/La Roche, Neomed Therapeutics1 Inc, Boehringer Ingelheim, Janssen Global Services, Alkermes, Thermo Fisher, MabDiscovery, Anaveon, Eli Lilly, Hengrui; Financial Interests, Personal, Invited Speaker: Ellipses Pharma, Seattle Genetics, Bristol-Myers Squibb, MSD, F-Star Therapeutics; Financial Interests, Institutional, Funding: Novartis, Roche, Thermo Fisher, AstraZeneca, Taiho. M.G. Krebs: Financial Interests, Personal, Advisory Board: Bayer, Roche, Janssen, Guardant Health; Financial Interests, Personal, Invited Speaker: Roche, Janssen; Financial Interests, Institutional, Expert Testimony: AstraZeneca; Financial Interests, Institutional, Advisory Board: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Blueprint, Astex, Bayer, BerGenBio, Carrick, Immutep, Janssen, Novartis, Nurix, Nuvalent, Pyramid Biosciences, Roche, Seattle Genetics, Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Novartis; Other, Personal, Other, Travel expenses for congress: Immutep, Janssen. H. Arkenau: Financial Interests, Personal and Institutional, Full or part-time Employment, Has stock options: Ellipses Pharma. L. Clark: Financial Interests, Personal and Institutional, Full or part-time Employment, Holds stock options: Ellipses Pharma; Financial Interests, Personal, Stocks/Shares: Autolus Pharma. G. Fisher: Financial Interests, Personal and Institutional, Full or part-time Employment, Has stock options: Ellipses Pharma. V. Subbiah: Financial Interests, Personal, Advisory Board, One time advisory board: Incyte, Novartis, Eli Lilly/ Loxo Oncology; Financial Interests, Personal, Advisory Board, One time ad board: Roche, Pfizer; Financial Interests, Personal, Advisory Board, Ad hoc advisory board: Relay Therapeutics; Financial Interests, Institutional, Invited Speaker, Research funding to conduct Clinical trial: Eli Lilly/Loxo Oncology,, Blueprint medicines, Novartis, Boston Pharmaceuticals, Pfizer, Turning Point Therapeutics, Amgen, Bayer, Roche/ Genentech, Exelixis, Berg Pharma, N W Biotherapeutics, Relay Therapeutics, AbbVie, Agensys, Inhibrx, Dragonfly therapeutics, Takeda; Financial Interests, Institutional, Invited Speaker, Research funding to conduct clinical trial: Shasqi; Other, Personal, Other, I am employed at the University of Texas MD Anderson Cancer Center: The University of Texas MD Anderson Cancer Center; Other, Personal, Other, I receive research funding from NCI: National Cancer Institute, USA.